Clinical Trials /

Combination Study for High Risk Multiple Myeloma Patients

NCT03104270

Description:

Despite the recent introduction of novel anti-multiple myeloma (MM) agents, high risk MM remains with poor prognosis and a therapeutic challenge. Elotuzumab (ELO) is a humanized monoclonal antibody that recognizes CS1/CD139, a molecule highly expressed in MM cells. The ELO (10 mg/kg), lenalidomide (LEN) and dexamethasone (DEX) combination achieves high overall response rates (ORR) and long progression-free survival (PFS) for patients with relapsed/refractory disease (RR) MM and those with impaired renal function. However, its efficacy for MM patients with high risk characteristics is still unknown. Pomalidomide (POM) is a recently approved immunomodulatory agent (IMiD) that produces response rates for high-risk RRMM patients when used in combination with DEX and other agents, including the proteasome inhibitor (PI) bortezomib (BTZ). POM has also demonstrated activity for LEN refractory patients. Carfilzomib (CFZ) is a potent second generation PI that has shown to be efficacious for IMiD and BTZ refractory patients as well as high risk patients carrying cytogenetic abnormalities. In this study, we propose to evaluate efficacy and safety of ELO in combination with POM, DEX and CFZ for high-risk RRMM patients.

Related Conditions:
  • Multiple Myeloma
  • Plasma Cell Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Study for High Risk Multiple Myeloma Patients
  • Official Title: A Phase 2 Trial of the Efficacy and Safety of Elotuzumab in Combination With Pomalidomide, Carfilzomib and Dexamethasone Among High Risk Relapsed/ Refractory Multiple Myeloma Patients

Clinical Trial IDs

  • ORG STUDY ID: CA204-187
  • NCT ID: NCT03104270

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
ElotuzumabBMS-901608Elo Pom Car and Dex
PomalidomideCC-4047, PomalystElo Pom Car and Dex
CarfilzomibKyprolisElo Pom Car and Dex
DexamethasoneSteroidElo Pom Car and Dex

Purpose

Despite the recent introduction of novel anti-multiple myeloma (MM) agents, high risk MM remains with poor prognosis and a therapeutic challenge. Elotuzumab (ELO) is a humanized monoclonal antibody that recognizes CS1/CD139, a molecule highly expressed in MM cells. The ELO (10 mg/kg), lenalidomide (LEN) and dexamethasone (DEX) combination achieves high overall response rates (ORR) and long progression-free survival (PFS) for patients with relapsed/refractory disease (RR) MM and those with impaired renal function. However, its efficacy for MM patients with high risk characteristics is still unknown. Pomalidomide (POM) is a recently approved immunomodulatory agent (IMiD) that produces response rates for high-risk RRMM patients when used in combination with DEX and other agents, including the proteasome inhibitor (PI) bortezomib (BTZ). POM has also demonstrated activity for LEN refractory patients. Carfilzomib (CFZ) is a potent second generation PI that has shown to be efficacious for IMiD and BTZ refractory patients as well as high risk patients carrying cytogenetic abnormalities. In this study, we propose to evaluate efficacy and safety of ELO in combination with POM, DEX and CFZ for high-risk RRMM patients.

Detailed Description

      This is a Phase 2, multicenter, open label, nonrandomized study with six patients safety
      lead-in cohort to evaluate efficacy and safety of elotuzumab in combination with
      pomalidomide, carfilzomib and dexamethasone among high risk relapsed and refractory multiple
      myeloma patients.

      This study will enroll previously treated patients that currently show evidence of
      progressive disease and have been diagnosed with high risk multiple myeloma. Thirty-nine
      patients will be enrolled in the study.

      First, six patients will be enrolled and used as a lead-in cohort for the safety evaluation
      and MTD re-determination (if necessary). The results of the safety lead-in cohort will be
      evaluated after the 6th patient has completed one full cycle of treatment. Recruitment of
      patients will be withheld during safety data analysis. Enrollment of the remaining 33
      patients will be contingent upon safety committee's decision.

      The study consists of: 1) a screening period; 2) up to eight 28-day treatment cycles; 3) a
      final assessment to occur 28 days after the end of the last treatment cycle; and 4) a
      follow-up period.

      All drugs will be administered on a 28-day cycle schedule throughout the study. Subjects
      eligible for this study will receive treatment with study drug for a maximum of eight 28-day
      treatment cycles. Subjects are to be treated for 8 cycles of therapy without demonstrating
      PD.
    

Trial Arms

NameTypeDescriptionInterventions
Elo Pom Car and DexExperimentalDrug dosing and administration: All drugs are administered on a 28-day cycle. Elotuzumab: 10 mg/kg IV on Days 1,8,15 and 22 Cycles 1 and 2. 20 mg/kg on Day 1 of Cycles 3 and beyond. Pomalidomide: 3 mg PO on days 1-21 Carfilzomib: 20 mg/m2 IV on days 1 of cycle 1. 56 mg/m2 IV on days 8 and 15 of cycle 1 and Days 1, 8 and 15 of the remaining seven cycles. Dexamethasone: On days 1,8,15,22 of Cycle 1-2 and day 1 of Cycle 3 and every day 1 thereafter, pre-treatment with 28 mg PO 3-24 hours prior to the start of ELO. On days 8,15,22 of Cycle 3 and beyond, 40mg of DEX PO or IV. On Day 8 and 15 of Cycle 3 and beyond, pre-treatment with DEX 40mg PO or IV at least 30 min and no more than 4 hours prior to the start of CFZ.
  • Elotuzumab
  • Pomalidomide
  • Carfilzomib
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must be adults (age ≥ 18 years at the time of signing the informed consent
             document) and must meet all of the following inclusion criteria to be enrolled in the
             study:

               1. ECOG/Zubrod performance status of 0-2 at study entry

               2. Has a diagnosis of high-risk MM by showing any of the following a-f criteria: :

                    1. Presence of conventional cytogenetic markers such as deletion of 17p-p53,
                       translocations involving t(14;16) and t(14;20)

                    2. Plasma cell leukemia (PCL) (> 2.0 × 109/L circulating plasma cells by
                       standard differential)

                    3. Extramedullary MM

                    4. Doubling in levels of a MM markers in the past 3 months such as any of the
                       following criteria alone or in combination: i) Serum M-protein ≥ 1.0 g/dL,
                       or ii) Urine M-protein ≥ 400 mg/24 hours, or iii) Only in patients who do
                       not meet i or ii, then use serum free light chain (SFLC) > 200 mg/L
                       (involved light chain) and an abnormal kappa/lambda ratio

                    5. Refractoriness to their most recent lenalidomide-containing regimen and
                       proteasome inhibitor-containing regimen.

                    6. Renal failure related to MM with creatinine clearance (CrCl) >15 mL/min but
                       <30 mL/min as calculated by Cockcroft-Gault equation (Appendix 14.8).

               3. Has previously received more than two lines of therapy including a
                  lenalidomide-containing regimen and proteasome inhibitor-containing regimen.

               4. Currently demonstrating progressive disease

               5. Life expectancy greater than 3 months

               6. Laboratory test results within these ranges at Screening and confirmed at
                  enrollment prior to drug dosing on Cycle 1 Day 1:

                    -  ANC ≥ 1.5 x 109/L; if the bone marrow is extensively infiltrated ( ≥ 70%
                       plasma cells) then ≥ 1.0 x 109/L

                    -  Platelet count ≥ 75 x 109/L; if the bone marrow is extensively infiltrated (
                       ≥ 70% plasma cells) then ≥ 50 x 109/L

                    -  Hemoglobin ≥ 8 g/dL

               7. Women of childbearing potential (WOCBP†) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
                  10-14 days prior to and again within 24 hours of starting study drug regimen

                  † A WOCBP (women of childbearing potential) is a sexually mature woman who: 1)
                  has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
                  naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
                  at any time in the preceding 24 consecutive months) WOCBP must agree to follow
                  instructions for method(s) of contraception for the duration of treatment with
                  study drug (s) plus 5 half-lives of study drug plus 30 days (duration of
                  ovulatory cycle) for a total of 120 days post-treatment completion. Subject must
                  either commit to continued abstinence from heterosexual intercourse or begin TWO
                  acceptable methods of birth control, one highly effective method and one
                  additional effective method AT THE SAME TIME, and at least 28 days before she
                  starts taking study drugs. WOCBP must also agree to ongoing pregnancy testing.
                  All subjects must be counseled at a minimum of every 28 days about pregnancy
                  precautions and risks of fetal exposure. See Section 10.3.5.2, Appendix 4 and
                  Appendix 5. Males who are sexually active with WOCBP must agree to follow
                  instructions for method(s) of contraception for the duration of treatment with
                  study drug plus 5 half-lives of the study drug plus 90 days (duration of sperm
                  turnover) for a total of 154 days post-treatment completion. Men must agree to
                  use a latex condom during sexual contact with a WOCBP even if they have had a
                  vasectomy. All subjects must be counseled at a minimum of every 28 days about
                  pregnancy precautions and risks of fetal exposure. See Section 10.3.5, Appendix 4
                  and Appendix 5

               8. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily as
                  prophylactic anticoagulation (subjects intolerant to ASA may use warfarin or low
                  molecular weight heparin)

               9. Written informed consent in accordance with federal, local, and institutional
                  guidelines

              10. Able to adhere to the study visit schedule and other protocol requirements

        Exclusion Criteria:

          -  Subjects meeting any of the following exclusion criteria are not to be enrolled in the
             study:

               1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
                  and skin changes) 19

               2. Waldenström's macroglobulinemia

               3. Received the following prior therapy:

                    1. Elotuzumab

                    2. Chemotherapy within 3 weeks of study drugs (6 weeks for nitrosourea,
                       melphalan or monoclonal antibodies)

                    3. Corticosteroids (>10 mg/daily prednisone or equivalent) within 3 weeks of
                       study drugs

                    4. Immunomodulatory therapy within one week before study drugs

                    5. Antibody therapy within 3 weeks before study drugs

                    6. Extensive radiation therapy (total maximum radiation doses of 50Gy to any
                       individual site or 30Gy for the disseminated MM of bone) within 3 weeks
                       before study drugs. Receipt of localized radiation therapy does not preclude
                       enrollment.

                    7. Cytotoxic chemotherapy with approved or investigational anticancer
                       therapeutics within 3 weeks prior to first dose

                    8. Use of any other experimental drug or therapy within 3 weeks of study drugs

               4. Received the following transplant therapies:

                    1. Less than 12 weeks from auto transplant

                    2. Less than 16 weeks from allo transplant

                    3. Less than 4 weeks since any plasmapheresis

               5. Major surgery within 4 weeks prior to first dose

               6. Impaired cardiac function or clinically significant cardiac diseases, including
                  any one of the following:

                    1. Myocardial infarction within last 6 months prior to enrollment

                    2. Active congestive heart failure (New York Heart Association (NYHA) Class III
                       or IV) heart failure

                    3. Uncontrolled angina and/or hypertension

                    4. Clinically significant pericardial disease

                    5. Severe uncontrolled ventricular arrhythmias

                    6. Echocardiogram or MUGA evidence of LVEF below institutional normal within 28
                       days prior to enrollment

                    7. Electrocardiographic evidence of acute ischemia or active conduction system
                       abnormalities. Prior to study entry, any ECG abnormality at Screening has to
                       be documented by the investigator as not medically relevant.

               7. Known or suspected amyloidosis

               8. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected for
                  albumin

               9. Acute active infection requiring systemic antibiotics, antiviral), or antifungal
                  agents

              10. Known positivity for human immunodeficiency virus (HIV)

              11. Known active hepatitis A,B or C virus infection

              12. Known active tuberculosis (TB) including subjects with latent TB or with the risk
                  factor for activation of latent TB.

              13. Patients with known cirrhosis

              14. Secondary non-hematologic malignancy within the past 3 years, except:

                    1. Adequately treated basal cell or squamous cell skin cancer

                    2. Carcinoma in situ of the cervix

                    3. Prostate cancer < Gleason score 6 or less with stable prostate-specific
                       antigen (PSA) levels over 12 months

                    4. Breast carcinoma in situ with full surgical resection

                    5. Treated medullary or papillary thyroid cancer

              15. Patients with myelodysplastic syndrome

              16. Prior cardio vascular accident (CVA) with persistent neurological deficit

              17. Significant neuropathy (Grades 3 to 4) within 14 days prior to first dose

              18. Peripheral neuropathy with pain ≥ G2 within 14 days prior to first dose

              19. Women who are pregnant and/or breast feeding

              20. Known hypersensitivity to dexamethasone

              21. Known history of allergy to Captisol® (a cyclodextrin derivative used to
                  solubilize carfilzomib)

              22. Known hypersensitivity to compounds of similar chemical or biological composition
                  to thalidomide

              23. The development of erythema nodosum if characterized by a desquamating rash while
                  taking thalidomide or similar drugs

              24. Hypersensitivity to any of the required concomitant drugs or supportive
                  treatments, including hypersensitivity to antiviral drugs.

              25. Ongoing graft-versus-host disease.

              26. Pleural effusions requiring thoracentesis or ascites requiring paracentesis
                  within 14 days prior to enrollment.

              27. Uncontrolled diabetes within 2 weeks prior to enrollment.

              28. Any other clinically significant medical disease or psychiatric condition that,
                  in the Investigator's opinion, may interfere with protocol adherence or a
                  patient's ability to give informed consent
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Time Frame:34 Months
Safety Issue:
Description:Occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria (If necessary re-define MTD via the number of dose-limiting toxicities (DLTs) per dose level, of elotuzumab in combination with pomalidomide, carfilzomib and dexamethasone for high risk RRMM patients (based on six patients lead-in cohort if necessary).

Secondary Outcome Measures

Measure:PFS
Time Frame:34 Months
Safety Issue:
Description:Progression-free survival (PFS): time from initiation of therapy to progressive disease or death from any cause, whichever comes first
Measure:DOR
Time Frame:34 Months
Safety Issue:
Description:Duration of response (DOR): time from the first response (> PR) to progressive disease
Measure:OS
Time Frame:34 Months
Safety Issue:
Description:Overall survival (OS): time from initiation of therapy to death from any cause or last follow-up visit.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncotherapeutics

Trial Keywords

  • Elotuzumab, Multiple Myeloma, Phase 2

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